A new study suggests that HIV drug development
should be focused on immune cells called macrophages, whose job is to “eat” invading
disease agents, instead of traditionally targeted T cells because that may take scientists a step closer to eradicating the disease.
The study led by researchers from the University of Florida and five other institutions was the largest of its kind. It showed that in HIV-infected diseased cells, such as cancer cells, almost all the virus was packed into macrophages.
The researchers observed that up to half of those macrophages were hybrids, formed when pieces of genetic material from several parent HIV viruses combined to form new strains.
They say that such “recombination” is responsible for formation of mutants that easily elude immune system surveillance and escape from anti-HIV drugs.
“Macrophages are these little factories producing new hybrid particles of the virus, making the virus probably even more aggressive over time. If we want to eradicate HIV we need to find a way to actually target the virus specifically infecting the macrophages,” said study co-author Dr. Marco Salemi, an assistant professor in the department of pathology, immunology and laboratory medicine at the UF College of Medicine.
The researchers used frozen post-autopsy tissue samples, pathology results and advanced computational techniques to study whether HIV populations that infect abnormal tissues are different from those that infect normal ones, and whether particular strains are associated with certain types of illness.
They analysed 780 HIV sequences from 53 normal and abnormal tissues from seven patients who had died between 1995 and 2003 from various AIDS-related conditions, including HIV-associated dementia, non-Hodgkin’s lymphoma and generalized infections throughout the body.
Four of the patients had been treated with highly active antiretroviral therapy, called HAART, at or near the time of death.
The research team compared brain and lymphoma tissues having heavy concentrations of macrophages with tissues from the spleen and lymph nodes that had a mix of HIV-infected macrophages and T cells.
The analyses revealed great diversity in the HIV strains present, with different tissues having hybrid viruses made up of slightly different sets of genes. A high frequency of such recombinant viruses was also found in tissues generally associated with disease processes, such as the meninges, spleen and lymph nodes.
Based on their observations, the researchers came to the conclusion that HIV-infected macrophages might be implicated in tumour-producing mechanisms.
They say that the higher frequency of recombinant virus in diseased tissues likely is because macrophages multiply as a result of an inflammatory response.
“The study points to macrophages as a site of recombination in active disease. So people can say this is one spot where these viruses come from,” said neurobiologist Dr. Kenneth C. Williams, a Boston College associate professor and AIDS expert who was not involved in the study.
T cells are an obvious target for HIV drug development because they die soon after infection, and are readily sampled from the blood and cultured. But although current drugs are effective at blocking infection of new cells and lowering viral loads to barely detectable levels, they never reduce the viral level in an infected person to zero.
Macrophages, on the other hand, do not die within days when infected by HIV. They live for several months, all the while being re-infected with multiple viruses of different genetic makeup. That situation is ripe for the emergence of hybrids.
“Most people who look at viral sequences assume that evolution of the virus is linear. In the real world that doesn’t happen — large parts of the virus are swapped in and out. This group has shown that in this model. It sort of overturns the old way of trying to match virus sequence with pathology,” Williams said.
The researchers are now developing macrophage-targeting drugs that, they believe, should be in human clinical trials
in a few years.